This invention relates to catalytic transfer hydrogenation, particularly in the presence of a complexed transition metal, and to a process of making optically active compounds.
According to a first aspect of the present invention there is provided a process for the transfer hydrogenation of a substrate wherein the substrate is reacted with a hydrogen donor in the presence of a transfer hydrogenation catalyst, characterised in that the substrate has the general formula 
wherein:
X represents NR3 or (NR4R5)+Qxe2x88x92;
Qxe2x88x92represents a monovalent anion;
R1 and R2 each independently represents a hydrogen atom, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group, a substituted carbonyl functional group, a substituted thiocarbonyl functional group or substituted imino functional group, R1 and R2 optionally being linked in such a way as to form an optionally substituted ring;
R3 and R4 represents xe2x80x94P(O)R6R7, xe2x80x94P(O)OR8OR9, xe2x80x94P(O)OR8OH, xe2x80x94P(O)(OH)2, xe2x80x94P(O)SR10SR11, xe2x80x94P(O)SR10SH, xe2x80x94P(O)(SH)2, xe2x80x94P(O)NR12R13NR14R15, xe2x80x94P(O)NR12R13NHR14, xe2x80x94P(O)NHR12NHR14, xe2x80x94P(O)NR12R13NH2, xe2x80x94P(O)NHR12NH2, xe2x80x94P(O)(NH2)2, xe2x80x94P(O)R6OR8, xe2x80x94P(O)R6OH, xe2x80x94P(O)R6SR10, xe2x80x94P(O)R6SH, xe2x80x94P(O)R6NR12R13, xe2x80x94P(O)R6NHR12, xe2x80x94P(O)R6NH2, xe2x80x94P(O)OR8SR10, xe2x80x94P(O)OR8SH, xe2x80x94P(O)OHSR10, xe2x80x94P(O)OHSH, xe2x80x94P(O)OR8NR12R13, xe2x80x94P(O)OR8NHR12, xe2x80x94P(O)OR8NH2, xe2x80x94P(O)OHNR12R13, xe2x80x94P(O)OHNHR12, xe2x80x94P(O)OHNH2, xe2x80x94P(O)SR10NR12R13, xe2x80x94P(O)SR10NHR12, xe2x80x94P(O)SR10NH2, xe2x80x94P(O)SHNR12R13, xe2x80x94P(O)SHNHR12, xe2x80x94P(O)SHNH2, xe2x80x94P(S)R6R7, xe2x80x94P(S)OR8OR9, xe2x80x94P(S)OR8OH, xe2x80x94P(S)(OH)2, xe2x80x94P(S)SR10SR11, xe2x80x94P(S)SR10SH, xe2x80x94P(S)(SH)2, xe2x80x94P(S)NR12R13NR14R15, xe2x80x94P(S)NR12R13NHR14, xe2x80x94P(S)NHR12NHR14, xe2x80x94P(S)NR12R13NH2, xe2x80x94P(S)NHR12NH2, xe2x80x94P(S)(NH2)2, xe2x80x94P(S)R6OR8, xe2x80x94P(S)R6OH, xe2x80x94P(S)R6SR10, xe2x80x94P(S)R6SH, xe2x80x94P(S)R6NR12R13, xe2x80x94P(S)R6NHR12, xe2x80x94P(S)R6NH2, xe2x80x94P(S)OR8SR10, xe2x80x94P(S)OHSR10, xe2x80x94P(S)OR8SH, xe2x80x94P(S)OHSH, xe2x80x94P(S)OR8NR12R13, xe2x80x94P(S)OR8NHR12, xe2x80x94P(S)OR8NH2, xe2x80x94P(S)OHNR12R13, xe2x80x94P(S)OHNHR12, xe2x80x94P(S)OHNH2, xe2x80x94P(S)SR10NR12R13, xe2x80x94P(S)SR10NHR12, xe2x80x94P(S)SR10NH2, xe2x80x94P(S)SHNR12R13, xe2x80x94P(S)SHNHR12, xe2x80x94P(S)SHNH2, xe2x80x94PR6R7, xe2x80x94POR8OR9, xe2x80x94PSR10SR11, xe2x80x94PNR12R13NR14R15, xe2x80x94PR6OR8, xe2x80x94PR6SR10, xe2x80x94PR6NR12R13, xe2x80x94POR8SR10, xe2x80x94POR8NR12R13, xe2x80x94PSR10NR12R13, xe2x80x94S(O)R16, xe2x80x94S(O)2R17, xe2x80x94COR18, xe2x80x94CO2R19, or SiR20R21R22;
R5 represents a hydrogen atom, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, or an optionally substituted heterocyclyl group;
R6 and R7 independently represent an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group or xe2x80x94Nxe2x95x90CR23R24 where R23 and R24 are as defined for R1; and
R8 to R22 each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, one or more of R1 and R6, R2 and R7, R6 and R7, R6 and R8, R6 and R10, R6 and R12, R1 and R8, R2 and R9, R8 and R9, R8 and R10, R8 and R12, R1 and R10, R2 and R11, R10 and R11, R10 and R12, R1 and R12, R2 and R13, R12 and R13, R1 and R14, R2 and R15, R14 and R15, R12 and R14, R1 and R16, R1 and R18, R1 and R19, R1 and R20, R2 and R21, R20 and R21 and R21 and R22 optionally being linked in such a way as to form an optionally substituted ring(s).
When X represents (NR4R5)+Qxe2x88x92, compounds of formula (1) are iminium salts. Iminium salts include protonated iminium salts and quaternary iminium salts. Quaternary iminium salts are represented by compounds of formula (I) in which R5 is not hydrogen.
Anions which may be represented by Qxe2x88x92 include halides, optionally substituted arylsulphonates, such as optionally substituted phenyl and naphthyl sulphonates, optionally substituted alkylsulphonates including halogenated alkylsulphonates, such as C1-20alkylsulphonates, optionally substituted carboxylates, such as C1-10 alkyl and aryl carboxylates, ions derived from the polyhalogenation of boron, phosphorous or antimony, and other common inorganic ions for example perchlorate. Particular examples of anions are bromide, chloride, iodide, hydrogen sulphate, tosylate, formate, acetate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, perchlorate, trifluoromethanesulphonate and trifluoroacetate. Preferred anions include bromide, chloride, iodide, formate and trifluoroacetate, and particularly preferred anions include iodide, formate and trifluoroacetate.
Hydrocarbyl groups which may be represented by one or more of R1, R2, and R5 to R24, include alkyl, alkenyl, alkynyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.
Alkyl groups which may be represented by one or more of R1, R2, and R5 to R24 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprise up to 10 branched chain carbon atoms, preferably up to 4 branched chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R1, R2, and R5 to R24 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.
Alkenyl groups which may be represented by one or more of R1, R2, and R5 to R24 include C2-20, and preferably C2-6 alkenyl groups. One or more carbon-carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups. When either of R1 or R2 represents an alkenyl group, a carbon-carbon double bond is preferably located at the position xcex2 to the Cxe2x95x90X moiety. When either of R1 or R2 represents an alkenyl group, the compound of formula (1) is preferably an xcex1,xcex2-unsaturated iminium compound.
Alkynyl groups which may be represented by one or more of R1, R2, and R5 to R24 include C2-20, and preferably C2-10 alkynyl groups. One or more carbon-carbon triple bonds may be present. The alkynyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkynyl groups include ethynyl, propyl and phenylethynyl groups. When either of R1 or R2 represents an alkynyl group, a carbon-carbon triple bond is preferably located at the position xcex2 to the Cxe2x95x90X moiety. When either of R1 or R2 represents an alkynyl group, the compound of formula (1) preferably has the triple bond in conjugation with the iminium group.
Aryl groups which may be represented by one or more of R1, R2, and R5 to R24 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R1, R2, and R5 to R24 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
Perhalogenated hydrocarbyl groups which may be represented by one or more of R1, R2, and R5 to R24 independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R1, R2, and R5 to R24 include xe2x80x94CF3 and xe2x80x94C2F5.
Heterocyclic groups which may be represented by one or more of R1, R2, and R5 to R24 independently include aromatic, saturated and partially unsaturated ring systems and may comprise 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. When either of R1 or R2 represents or comprises a heterocyclic group, the atom in R1 or R2 bonded to the Cxe2x95x90X group is preferably a carbon atom. Examples of heterocyclic groups which may be represented by R1, R2, and R5 to R24 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.
When any of R1, R2, and R5 to R24 is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivety of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, imino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carboxy, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R1 above. One or more substituents may be present. R1, R2, and R5 to R24 may each contain one or more chiral centres.
When any of R1 and R2, R1 and R6, R2 and R7, R1 and R7, R6 and R8, R6 and R10, R6 and R12, R1 and R8, R2 and R9, R8 and R9, R8 and R10, R8 and R12, R1 and R10, R2 and R11, R10 and R11, R10 and R12, R1 and R12, R2 and R13, R12 and R13, R1 and R14, R2 and R15 R14 and R15, R12 and R14, R1 and R16, R1 and R18, R1 and R19, R1 and R20, R2 and R21, R20 and R21 and R21 and R22 are linked in such a way that when taken together with the atoms to which they are attached that a ring is formed, it is preferred that these be 5, 6 or 7 membered rings. The rings formed in this way may additionally be fused to each other or to other ring systems. Examples of rings which may be so formed include oxazaphospholidenes, dioxaphospholans, phospholans, phosphorinans, dioxaphosphorinans and benzodioxaphospholans. The rings may be optionally substituted or may be fused to other rings.
Substituted carbonyl functional groups which may be represented by one or more of R1, R2, R23 and R24 include aldehyde, ketone, acid and ester groups, for example xe2x80x94COR25, xe2x80x94CO2R25, and xe2x80x94CONR25R26 wherein R25 and R26 independently represent hydrogen, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group as defined hereinbefore for R5.
Substituted thiocarbonyl functional groups which may be represented by one or more of R1, R2, R23 and R24 include thioaldehyde, thioketone, thioacid and thioester groups, for example xe2x80x94CSR25, xe2x80x94CSOR25 and xe2x80x94CSNR25R26 wherein R25 and R26 independently represent hydrogen; an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group as defined hereinbefore for R5.
Substituted imino functional groups which may be represented by one or more of R1, R2, R23 and R24 include unsubstituted imines and substituted imine and iminium groups, for example xe2x80x94C(xe2x95x90NR25)R26 and xe2x80x94C(xe2x95x90X)R26 wherein X is as hereinbefore defined and R25 and R26 independently represent hydrogen, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group as defined hereinbefore for R5.
When one of R1 or R2 is represented by a group selected from a carbonyl functional group, a thiocarbonyl functional group and an imino functional group, it is preferred that the other of R1 or R2 is represented by a hydrogen atom, an optionally substituted hydrocarbyl group, a perhalogenated hydrocarbyl group or an optionally substituted heterocyclyl group.
When one of R23 or R24 is represented by a group selected from a carbonyl functional group, a thiocarbonyl functional group and an imino functional group, it is preferred that the other of R23 or R24 being represented by a hydrogen atom, an optionally substituted hydrocarbyl group, a perhalogenated hydrocarbyl group or an optionally substituted heterocyclyl group.
When one of R1 and R6 or R2 and R7 is linked in such a way as to form an optionally substituted ring and the ring so formed contains more than one carbon nitrogen double bond (imino group), it is preferred that nitrogen-phosphorous heterocycle so formed has both nitrogens are attached to a common phosphorous atom. Examples of such nitrogen-phosphorous heterocycles include 
In certain preferred embodiments, R1, R2, and R5 to R24 are all independently C1-6alkyl or are a combination of aryl, particularly phenyl, C1-6alkyl and C6-10aralkyl. Substituents may be present, particularly substituents para to the Cxe2x95x90X group when one or more of R1, R2, and R5 to R24 is a phenyl group.
In many preferred embodiments, when R3 or R4 is a group selected from xe2x80x94P(O)R6R7, xe2x80x94P(O)OR8OR9, xe2x80x94P(O)OR8OH, xe2x80x94P(O)SR10SR11, xe2x80x94P(O)SR10SH, xe2x80x94P(O)NR12R13NR14R15, xe2x80x94P(O)NR12R13NHR14, xe2x80x94P(O)NHR12NHR14, xe2x80x94P(O)NR12R13NH2, xe2x80x94P(O)NHR12NH2, xe2x80x94P(O)R6OR8, xe2x80x94P(O)R6OH, xe2x80x94P(O)R6SR10, xe2x80x94P(O)R6SH, xe2x80x94P(O)R6NR12R13, xe2x80x94P(O)R6NHR12, xe2x80x94P(O)R6NH2, xe2x80x94P(O)OR8SR10, xe2x80x94P(O)OR8SH, xe2x80x94P(O)OHSR10, xe2x80x94P(O)OR8NR12R13, xe2x80x94P(O)OR8NHR12, xe2x80x94P(O)OR8NH2, xe2x80x94P(O)OHNR12R13, xe2x80x94P(O)OHNHR12, xe2x80x94P(O)SR10NR12R13, xe2x80x94P(O)SR10NHR12, xe2x80x94P(O)SR10NH2, xe2x80x94P(O)SHNR12R13, xe2x80x94P(O)SHNHR12, xe2x80x94P(S)R6R7, xe2x80x94P(S)OR8OR9, xe2x80x94P(S)OR8OH, xe2x80x94P(S)SR10SR11, xe2x80x94P(S)SR10SH, xe2x80x94P(S)(SH)2, xe2x80x94P(S)NR12R13NR14R15, xe2x80x94P(S)NR12R13NHR14, xe2x80x94P(S)NHR12NHR14, xe2x80x94P(S)NR12R13NH2, xe2x80x94P(S)NHR12NH2, xe2x80x94P(S)R6OR8, xe2x80x94P(S)R6OH, xe2x80x94P(S)R6SR10, xe2x80x94P(S)R6SH, xe2x80x94P(S)R6N12R13, xe2x80x94P(S)R6NHR12, xe2x80x94P(S)R6NH2, xe2x80x94P(S)OR8SR10, xe2x80x94P(S)OHSR10, xe2x80x94P(S)OR8SH, xe2x80x94P(S)OR8NR12R13, xe2x80x94P(S)OR8NHR12, xe2x80x94P(S)OR8NH2, xe2x80x94P(S)OHNR12R13, xe2x80x94P(S)OHNHR12, xe2x80x94P(S)SR10NR12R13, xe2x80x94P(S)SR10NHR12, xe2x80x94P(S)SR10NH2, xe2x80x94P(S)SHNR12R13, xe2x80x94P(S)SHNHR12, xe2x80x94PR6R7, xe2x80x94POR8OR9, xe2x80x94PSR10SR11, xe2x80x94PNR12R13NR14R15, xe2x80x94PR6OR8, xe2x80x94PR6SR10, xe2x80x94PR6NR12R13, xe2x80x94POR8SR10, xe2x80x94POR8NR12R13, xe2x80x94PSR10NR12R13, or SiR20R21R22, the groups R6 to R15 and R20 to R22 are selected to be the same and more preferably they are selected to all be phenyl or ethyl groups. This may have the advantage that synthesis of intermediates is simplified. However, in certain embodiments it may be preferable for more than one of the groups R6 to R15 or R20 to R22 present to be different, in which case it is most preferable that each R6 to R15 or R20 to R22 group present is selected to be one of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, t-butyl or phenyl.
Preferably, R3 and R4 are electron withdrawing groups, such as xe2x80x94P(O)R6R7, xe2x80x94P(O)OR8OR9, xe2x80x94P(O)OR8OH, xe2x80x94P(O)(OH)2, xe2x80x94P(O)SR10SR11, xe2x80x94P(O)SR10SH, xe2x80x94P(O)(SH)2, xe2x80x94P(O)NR12R13NR14R15, xe2x80x94P(O)NR12R13NHR14, xe2x80x94P(O)NHR12NHR14, xe2x80x94P(O)NR12R13NH2, xe2x80x94P(O)NHR12NH2, xe2x80x94P(O)(NH2)2, xe2x80x94P(O)R6OR8, xe2x80x94P(O)R6OH, xe2x80x94P(O)R6SR10, xe2x80x94P(O)R6SH, xe2x80x94P(O)R6NR12R13, xe2x80x94P(O)R6NHR12, xe2x80x94P(O)R6NH2, xe2x80x94P(O)OR8SR10, xe2x80x94P(O)OR8SH, xe2x80x94P(O)OHSR10, xe2x80x94P(O)OHSH, xe2x80x94P(O)OR8NR12R13, xe2x80x94P(O)OR8NHR12, xe2x80x94P(O)OR8NH2, xe2x80x94P(O)OHNR12R13, xe2x80x94P(O)OHNHR12, xe2x80x94P(O)OHNH2, xe2x80x94P(O)SR10NR12R13, xe2x80x94P(O)SR10NHR12, xe2x80x94P(O)SR10NH2, xe2x80x94P(O)SHNR12R13, xe2x80x94P(O)SHNHR12, xe2x80x94P(O)SHNH2, xe2x80x94P(S)R6R7, xe2x80x94P(S)OR8OR9, xe2x80x94P(S)OR8OH, xe2x80x94P(S)(OH)2, xe2x80x94P(S)SR10SR11, xe2x80x94P(S)SR10SH, xe2x80x94P(S)(SH)2, xe2x80x94P(S)NR12R13NR14R15, xe2x80x94P(S)NR12R13NHR14, xe2x80x94P(S)NHR12NHR14, xe2x80x94P(S)NR12R13NH2, xe2x80x94P(S)NHR12NH2, xe2x80x94P(S)(NH2)2, xe2x80x94P(S)R6OR8, xe2x80x94P(S)R6OH, xe2x80x94P(S)R6SR10, xe2x80x94P(S)R6SH, xe2x80x94P(S)R6NR12R13, xe2x80x94P(S)R6NHR12, xe2x80x94P(S)R6NH2, xe2x80x94P(S)OR8SR10, xe2x80x94P(S)OHSR10, xe2x80x94P(S)OR8SH, xe2x80x94P(S)OHSH, xe2x80x94P(S)OR8NR12R13, xe2x80x94P(S)OR8NHR12, xe2x80x94P(S)OR8NH2, xe2x80x94P(S)OHNR12R13, xe2x80x94P(S)OHNHR12, xe2x80x94P(S)OHNH2, xe2x80x94P(S)SR10NR12R13, xe2x80x94P(S)SR10NHR12, xe2x80x94P(S)SR10NH2, xe2x80x94P(S)SHNR12R13, xe2x80x94P(S)SHNHR12, xe2x80x94P(S)SHNH2, xe2x80x94S(O)R16, xe2x80x94S(O)2R17 xe2x80x94COR18, and xe2x80x94CO2R19. It is especially preferred that R3 and R4 are groups selected from xe2x80x94P(O)R6R7, xe2x80x94P(O)OR8OR9, xe2x80x94P(O)R6OR8, xe2x80x94P(S)R6R7, xe2x80x94P(S)OR8OR9, xe2x80x94P(S)R6OR8, xe2x80x94S(O)R16, xe2x80x94COR18, and xe2x80x94CO2R19. It is most preferred that R3 and R4 are groups selected from xe2x80x94P(O)R6R7, xe2x80x94P(O)OR8OR9.
When either R3 or R4 is a group selected from xe2x80x94P(O)R6R7, xe2x80x94P(O)OR8OR9, xe2x80x94P(O)OR8OH, xe2x80x94P(O)SR10SR11, xe2x80x94P(O)SR10SH, xe2x80x94P(O)NR12R13NR14R15, xe2x80x94P(O)NR12R13NHR14, xe2x80x94P(O)NHR12NHR14, xe2x80x94P(O)NR12R13NH2, xe2x80x94P(O)NHR12NH2, xe2x80x94P(O)R6OR8, xe2x80x94P(O)R6OH, xe2x80x94P(O)R6SR10, xe2x80x94P(O)R6SH, xe2x80x94P(O)R6NR12R13, xe2x80x94P(O)R6NHR12, xe2x80x94P(O)R6NH2, xe2x80x94P(O)OR8SR10, xe2x80x94P(O)OR8SH, xe2x80x94P(O)OHSR10, xe2x80x94P(O)OR8NR12R13, xe2x80x94P(O)OR8NHR12, xe2x80x94P(O)OR10NH2, xe2x80x94P(O)OHNR12R13, xe2x80x94P(O)OHNHR12, xe2x80x94P(O)SR10NR12R13, xe2x80x94P(O)SR10NHR12, xe2x80x94P(O)SR10NH2, xe2x80x94P(O)SHNR12R13, xe2x80x94P(O)SHNHR12, xe2x80x94P(S)R6R7, xe2x80x94P(S)OR8OR9, xe2x80x94P(S)OR8OH, xe2x80x94P(S)SR10SR11, xe2x80x94P(S)SR10SH, xe2x80x94P(S)(SH)2, xe2x80x94P(S)NR12R13NR14R15, xe2x80x94P(S)NR12R13NHR14, xe2x80x94P(S)NHR12NHR14, xe2x80x94P(S)NR12R13NH2, xe2x80x94P(S)NHR12NH2, xe2x80x94P(S)R6OR8, xe2x80x94P(S)R6OH, xe2x80x94P(S)R6SR10, xe2x80x94P6SH, xe2x80x94P(S)R6NR12R13, xe2x80x94P(S)R6NHR12, xe2x80x94P(S)R6NH2, xe2x80x94P(S)OR8SR10, xe2x80x94P(S)OHSR10, xe2x80x94P(S)OR8SH, xe2x80x94P(S)OR8NR12R13, xe2x80x94P(S)OR8NHR12, xe2x80x94P(S)OR8NH2, xe2x80x94P(S)OHNR12R13, xe2x80x94P(S)OHNHR12, xe2x80x94P(S)SR10NR12R13, xe2x80x94P(S)SR10NHR12, xe2x80x94P(S)SR10NH2, xe2x80x94P(S)SHNR12R13, xe2x80x94P(S)SHNHR12, xe2x80x94PR6R7, xe2x80x94POR8OR9, xe2x80x94PSR10SR11, xe2x80x94PNR12R13NR14R15, xe2x80x94PR6OR8, xe2x80x94PR6SR10, xe2x80x94PR6NR12R13, xe2x80x94POR8SR10, xe2x80x94POR8NR12R13, xe2x80x94PSR10NR12R13, xe2x80x94S(O)R16, xe2x80x94S(O)2R17, xe2x80x94COR18, xe2x80x94CO2R19, it is preferred that the groups represented by R6 to R19 are independently selected from alkyl or aryl groups, for example methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, t-butyl and phenyl groups, and preferably C1-6alkyl or C6-12aryl groups.
The groups R6 to R22 may contain chiral centres, or may be selected such that the atom to which they are bonded is a chiral centre.
In certain preferred embodiments, one of R1 and R2 is an alkyl group and the other is aryl or heterocyclyl, X is NR3 where R3 is either xe2x80x94P(O)R6R7 or xe2x80x94P(O)OR8OR9 wherein R6 to R9 is an alkyl or aryl group, more preferably a C1-4alkyl group, a phenyl group or a phenyl group substituted with one or more C1-4alkyl groups.
Most advantageously, the compound of formula (1) is prochiral, such that the hydrogenated product comprises a chiral atom to which R1, R2 and X are each bonded. Such an asymmetric transfer hydrogenation process forms an especially preferred aspect of the present invention. Most commonly, when the compound of formula (1) is prochiral, R1 and R2 are different, and neither is hydrogen. Preferably, one of R1 and R2 is aliphatic and the other is aryl or heterocyclyl.
Examples of compounds of formula (1) include 
wherein:
Ra=Ph, Naphthyl, CH2Ph, hexyl, iPr, tBu, Et, or Me
Rb=Ph, Naphthyl, CH2Ph, hexyl, iPr, tBu, Et, or Me
Rc=Ph, Naphthyl, CH2Ph, hexyl, iPr, tBu, Et, or Me; and
Rd=PO(Ph)2, or PO(Et)2.
Hydrogen donors include hydrbgen, primary and secondary alcohols, primary and secondary amines, carboxylic acids and their esters and amine salts, readily dehydrogenatable hydrocarbons, clean reducing agents, and any combination thereof.
Primary and secondary alcohols which may be employed as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 2 to 7 carbon atoms, and more preferably 3 or 4 carbon atoms. Examples of primary and secondary alcohols which may be represented as hydrogen donors include methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, butan-2-ol, cyclopentanol, cyclohexanol, benzylalcohol, and menthol. When the hydrogen donor is an alcohol, secondary alcohols are preferred, especially propan-2-ol and butan-2-ol.
Primary and secondary amines which may be employed as hydrogen donors comprise commonly from 1 to 20 carbon atoms, preferably from 2 to 14 carbon atoms, and more preferably 3 or 8 carbon atoms. Examples of primary and secondary amines which may be represented as hydrogen donors include ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, dihexylamine, diethylamine, dipropylamine, di-isopropylamine, dibutylamine, di-isobutylamine, dihexylamine, benzylamine, dibenzylamine and piperidine. When the hydrogen donor is an amine, primary amines are preferred, especially primary amines comprising a secondary alkyl group, particularly isopropylamine and isobutylamine.
Carboxylic acids or their esters which may be employed as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 1 to 3 carbon atoms. In certain embodiments, the carboxylic acid is advantageously a beta-hydroxy-carboxylic acid. Esters may be derived from the carboxylic acid and a C1-10 alcohol. Examples of carboxylic acids which may be employed as hydrogen donors include formic acid, lactic acid, ascorbic acid and mandelic acid. The most preferred carboxylic acid is formic acid. In certain preferred embodiments, when a carboxylic acid is employed as hydrogen donor, at least some of the carboxylic acid is preferably present as salt, preferably an amine, ammonium or metal salt. Preferably, when a metal salt is present the metal is selected form the alkali or alkaline earth metals of the periodic table, and more preferably is selected from the group I elements, such as lithium, sodium or potassium. Amines which may be used to form such salts include both aromatic and non-aromatic amines, also primary, secondary and tertiary amines and comprise typically from 1 to 20 carbon atoms. Tertiary amines, especially trialkylamines, are preferred. Examples of amines which may be used to form salts include trimethylamine, triethylamine, di-isopropylethylamine and pyridine. The most preferred amine is triethylamine. When at least some of the carboxylic acid is present as an amine salt, particularly when a mixture of formic acid and triethylamine is employed, the mole ratio of acid to amine is between 1:1 and 50:1 and preferably between 1:1 and 10:1, and most preferably about 5:2. When at least some of the carboxylic acid is present as a metal salt, particularly when a mixture of formic acid and a group I metal salt is employed, the mole ratio of acid to metal ions present is between 1:1 and 50:1 and preferably between 1:1 and 10:1, and most preferably about 2:1. The ratios of acid to salts may be maintained during the course of the reaction by the addition of either component, but usually by the addition of the carboxylic acid.
Readily dehydrogenatable hydrocarbons which may be employed as hydrogen donors comprise hydrocarbons which have a propensity to aromatise or hydrocarbons which have a propensity to form highly conjugated systems. Examples of readily dehydrogenatable hydrocarbons which may be employed by as hydrogen donors include cyclohexadiene, cyclohexene, tetralin, dihydrofuran and terpenes.
Clean reducing agents which may be represented as hydrogen donors comprise reducing agents with a high reduction potential, particularly those having a reduction potential relative to the standard hydrogen electrode of greater than about xe2x88x920.1 eV, often greater than about xe2x88x920.5 eV, and preferably greater than about xe2x88x921 eV. Examples of clean reducing agents which may be represented as hydrogen donors include hydrazine and hydroxylamine.
The most preferred hydrogen donors are propan-2-ol, butan-2-ol, triethylammonium formate and a mixture of triethylammonium formate and formic acid.
Transfer hydrogenation catalysts may include such catalysts such as a) the chiral Ruthenium (II) catalysts developed for ketone reduction which are disclosed in Chem. Rev., 1998, 98, 2607 see Table 2; b) the Zhang tridentate bis(oxazolinylmethyl)amine catalysts and related catalysts as disclosed in J. Am. Chem. Soc., 1998, 120, 3817, Tet. Let., 1997, 38(37), 6565 and in WO99/24410 (particularly the bis(phenyloxazolin-2-yl)amine and related catalysts discussed therein); and c) the transition metal, particularly group VIII metal, complexes with chiral ligands of formula 
wherein AR is any aromatic or ring structure and Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 are each independently selected from aryl, alkyl, aralkyl, ring-substituted aralkyl, substituted aryl and combinations thereof as disclosed in U.S. Pat. No. 5,767,276, the catalysts of a), b) and c) being incorporated herein by reference.
Preferred transfer hydrogenation catalysts for use in the process of the present invention have the general formula: 
wherein:
R27 represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand;
A represents xe2x80x94NR28xe2x80x94, xe2x80x94NR29xe2x80x94, xe2x80x94NHR28, xe2x80x94NR28R29 or xe2x80x94NR29R30 where R28 is H, C(O)R30, SO2R30, C(O)NR30R34, C(S)NR30R34, C(xe2x95x90NR34)SR35 or C(xe2x95x90NR34)OR35, R29 and R30, each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R34 and R35 are each independently hydrogen or a group as defined for R30;
B represents xe2x80x94Oxe2x80x94, xe2x80x94OH, OR31, xe2x80x94Sxe2x80x94, xe2x80x94SH, SR31, xe2x80x94NR31xe2x80x94, xe2x80x94NR32xe2x80x94, xe2x80x94NHR32, xe2x80x94NR31R32, xe2x80x94NR31R33, xe2x80x94PR31xe2x80x94 or xe2x80x94PR31 R33 where R32 is H, C(O)R33, SO2R33, C(O)NR33R36, C(S)NR33R36, C(xe2x95x90NR36)SR37 or C(xe2x95x90NR36)OR37, R31 and R33 each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R36 and R37 are each independently hydrogen or a group as defined for R33;
E represents a linking group;
M represents a metal capable of catalysing transfer hydrogenation; and
Y represents an anionic group, a basic ligand or a vacant site;
provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.
The catalytic species is believed to be substantially as represented in the above formula. It may be introduced on a solid support.
Optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or optionally substituted heterocyclyl groups which may be represented by R29-31 or R33-35 are as defined hereinbefore for R5.
The neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl ligand which may be represented by R27 includes optionally substituted aryl and alkenyl ligands.
Optionally substituted aryl ligands which may be represented by R27 may contain 1 ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic rings. Preferably, the ligand comprises a 6 membered aromatic ring. The ring or rings of the aryl ligand are often substituted with hydrocarbyl groups. The substitution pattern and the number of substituents will vary and may be influenced by the number of rings present, but often from 1 to 6 hydrocarbyl substituent groups are present, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl, menthyl, neomenthyl and phenyl. Particularly when the aryl ligand is a single ring, the ligand is preferably benzene or a substituted benzene. When the ligand is a perhalogenated hydrocarbyl, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Benzene, p-cymyl, mesitylene and hexamethylbenzene are especially preferred ligands.
Optionally substituted alkenyl ligands which may be represented by R27 include C2-30, and preferably C6-12, alkenes or cycloalkenes with preferably two or more carbon-carbon double bonds, preferably only two carbon-carbon double bonds. The carbon-carbon double bonds may optionally be conjugated to other unsaturated systems which may be present, but are preferably conjugated to each other. The alkenes or cycloalkenes may be substituted preferably with hydrocarbyl substituents. When the alkene has only one double bond, the optionally substituted alkenyl ligand may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl. Examples of optionally substituted alkenyl ligands include cyclo-octa-1,5-diene and 2,5-norbornadiene. Cyclo-octa-1,5-diene is especially preferred.
Optionally substituted cyclopentadienyl groups which may be represented by R27 includes cyclopentadienyl groups capable of eta-5 bonding. The cyclopentadienyl group is often substituted with from 1 to 5 hydrocarbyl groups, preferably with 3 to 5 hydrocarbyl groups and more preferably with 5 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl and phenyl. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Examples of optionally substituted cyclopentadienyl groups include cyclopentadienyl, pentamethyl-cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl, neomenthyl-tetraphenylcyclopentadienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl is especially preferred.
When either A or B is an amide group represented by xe2x80x94NR28xe2x80x94, xe2x80x94NHR28, NR28R29, xe2x80x94NR32xe2x80x94, xe2x80x94NHR32 or NR31R32 wherein R29 and R31 are as hereinbefore defined, and where R28 or R32 is an acyl group represented by xe2x80x94C(O)R30 or xe2x80x94C(O)R33, R30 and R33 independently are often linear or branched C1-7alkyl, C1-8-cycloalkyl or aryl, for example phenyl. Examples of acyl groups which may be represented by R28 or R33 include benzoyl, acetyl and halogenoacetyl, especially trifluoroacetyl, groups.
When either A or B is present as a sulphonamide group represented by xe2x80x94NR28xe2x80x94, xe2x80x94NHR28, NR28R29, xe2x80x94NR32xe2x80x94, xe2x80x94NHR32 or NR31R32 wherein R29 and R31 are as hereinbefore defined, and where R28 or R32 is a sulphonyl group represented by xe2x80x94S(O)2R30 or xe2x80x94S(O)2R33, R30 and R33 independently are often linear or branched C1-8alkyl, C1-8cycloalkyl or aryl, for example phenyl. Preferred sulphonyl groups include methanesulphonyl, trifluoromethanesulphonyl and especially p-toluenesulphonyl groups and naphthylsulphonyl groups.
When either of A or B is present as a group represented by xe2x80x94NR28xe2x80x94, xe2x80x94NHR28, NR28R29, xe2x80x94NR32xe2x80x94, xe2x80x94NHR32 or NR31R32 wherein R29 and R31 are as hereinbefore defined, and where R28 or R32 is a group represented by C(O)NR30R34, C(S)NR30R34, C(xe2x95x90NR34)SR35, C(xe2x95x90NR34)OR35, C(O)NR33R36, C(S)NR33R36, C(xe2x95x90NR36)SR37 or C(xe2x95x90NR36)OR37, R30 and R33 independently are often linear or branched C1-8alkyl, such as methyl, ethyl, isopropyl, C1-8cycloalkyl or aryl, for example phenyl, groups and R34-37 are often each independently hydrogen or linear or branched C1-8alkyl, such as methyl, ethyl, isopropyl, C1-8cycloalkyl or aryl, for example phenyl, groups.
When B is present as a group represented by xe2x80x94OR31, xe2x80x94SR31, xe2x80x94PR31xe2x80x94 or xe2x80x94PR31R33, R31 and R33 independently are often linear or branched C1-4alkyl, such as methyl, ethyl, isopropyl, C1-8cycloalkyl or aryl, for example phenyl.
It will be recognised that the precise nature of A and B will be determined by whether A and/or B are formally bonded to the metal or are coordinated to the metal via a lone pair of electrons.
The groups A and B are connected by a linking group E. The linking group E achieves a suitable conformation of A and B so as to allow both A and B to bond or coordinate to the metal, M. A and B are commonly linked through 2, 3 or 4 atoms. The atoms in E linking A and B may carry one or more substituents. The atoms in E, especially the atoms alpha to A or B, may be linked to A and B, in such a way as to form a heterocyclic ring, preferably a saturated ring, and particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other rings. Often the atoms linking A and B will be carbon atoms. Preferably, one or more of the carbon atoms linking A and B will carry substituents in addition to A or B. Substituent groups include those which may substitute R1, as defined above. Advantageously, any such substituent groups are selected to be groups which do not coordinate with the metal, M. Preferred substituents include halogen, cyano, nitro, sulphonyl, hydrocarbyl, perhalogenated hydrocarbyl and heterocyclyl groups as defined above. Most preferred substituents are C1-6 alkyl groups, and phenyl groups. Most preferably, A and B are linked by two carbon atoms, and especially an optionally substituted ethyl moiety. When A and B are linked by two carbon atoms, the two carbon atoms linking A and B may comprise part of an aromatic or aliphatic cyclic group, particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other such rings. Particularly preferred are embodiments in which E represents a 2 carbon atom separation and one or both of the carbon atoms carries an optionally substituted aryl group as defined above or E represents a 2 carbon atom separation which comprises a cyclopentane or cyclohexane ring, optionally fused to a phenyl ring.
E preferably comprises part of a compound having at least one stereospecific centre. Where any or all of the 2, 3 or 4 atoms linking A and B are substituted so as to define at least one stereospecific centre on one or more of these atoms, it is preferred that at least one of the stereospecific centres be located at the atom adjacent to either group A or B. When at least one such stereospecific centre is present, it is advantageously present in an enantiomerically purified state.
When B represents xe2x80x94Oxe2x80x94 or xe2x80x94OH, and the adjacent atom in E is carbon, it is preferred that B does not form part of a carboxylic group.
Compounds which may be represented by A-E-B, or from which A-E-B may be derived by deprotonation, are often aminoalcohols, including 4-aminoalkan-1-ols, 1-aminoalkan-4-ols, 3-aminoalkan-1-ols, 1-aminoalkan-3-ols, and especially 2-aminoalkan-1-ols, 1-aminoalkan-2-ols, 3-aminoalkan-2-ols and 2-aminoalkan-3-ols, and particularly 2-aminoethanols or 3-aminopropanols, or are diamines, including 1,4-diaminoalkanes, 1,3-diaminoalkanes, especially 1,2- or 2,3-diaminoalkanes and particularly ethylenediamines. Further aminoalcohols that may be represented by A-E-B are 2-aminocyclopentanols and 2-aminocyclohexanols, preferably fused to a phenyl ring. Further diamines that may be represented by A-E-B are 1,2-diaminocyclopentanes and 1,2-diaminocyclohexanes, preferably fused to a phenyl ring. The amino groups may advantageously be N-tosylated. When a diaimine is represented by A-E-B, preferably at least one amino group is N-tosylated. The aminoalcohols or diamines are advantageously substituted, especially on the linking group, E, by at least one alkyl group, such as a C1-4-alkyl, and particularly a methyl, group or at least one aryl group, particularly a phenyl group.
Specific examples of compounds which can be represented by A-E-B and the protonated equivalents from which they may be derived are: 
Preferably, the enantiomerically and/or diastereomerically purified forms of these are used. Examples include (1S,2R)-(+)-norephedrine, (1R,2S)-(+)-cis-1-amino-2-indanol, (1S,2R)-2-amino-1,2-diphenylethanol, (1S,2R)-(xe2x88x92)-cis-1-amino-2-indanol, (1R,2S)-(xe2x88x92)-norephedrine, (S)-(+)-2-amino-1-phenylethanol, (1R,2S)-2-amino-1,2-diphenylethanol, N-tosyl-(1R,2R)-1,2-diphenylethylenediamine, N-tosyl-(1S,2S)-1,2-diphenylethylenediamine, (1R,2S)-cis-1,2-indandiamine, (1S,2R)-cis-1,2-indandiamine, (R)-(xe2x88x92)-2-pyrrolidinemethanol and (S)-(+)-2-pyrrolidinemethanol.
Metals which may be represented by M include metals which are capable of catalysing transfer hydrogenation. Preferred metals include transition metals, more preferably the metals in Group VIII of the Periodic Table, especially ruthenium, rhodium or iridium. When the metal is ruthenium it is preferably present in valence state II. When the metal is rhodium or iridium it is preferably present in valence state I when R27 is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and preferably present in valence state III when R27 is an optionally substituted cyclopentadienyl ligand.
Anionic groups which may be represented by Y include hydride, hydroxy, hydrocarbyloxy, hydrocarbylamino and halogen groups. Preferably when a halogen is represented by Y, the halogen is chloride. When a hydrocarbyloxy or hydrocarbylamino group is represented by Y, the group may be derived from the deprotonation of the hydrogen donor utilised in the reaction.
Basic ligands which may be represented by Y include water, C1-4 alcohols, C1-8 primary or secondary amines, or the hydrogen donor which is present in the reaction system. A preferred basic ligand represented by Y is water.
Most preferably, the nature of A-E-B, R27 and Y are chosen such that the catalyst is chiral. When such is the case, an enantiomerically and/or diastereomerically purified form is preferably employed. Such catalysts are most advantageously employed in asymmetric transfer hydrogenation processes. In many embodiments, the chirality of the catalyst is derived from the nature of A-E-B.
Examples of catalysts which may be employed in the process of the present invention include 
The process is carried out preferably in the presence of a base, especially when Y is not a vacant site. The pKa of the base is preferably at least 8.0, especially at least 10.0. Convenient bases are the hydroxides, alkoxides and carbonates of alkali metals; tertiary amines and quaternary ammonium compounds. Preferred bases are sodium 2-propoxide and triethylamine. When the hydrogen donor is not an acid, the quantity of base used can be up to 10.0, commonly up to 5.0, often up to 3.0, frequently up to 2.5 and especially in the range 1.0 to 3.5, by moles of the catalyst. When the hydrogen donor is an acid, the catalyst may be contacted with a base prior to the introduction of the hydrogen donor. In such a case, the mole ratio of base to catalyst prior to the introduction of the hydrogen donor is often from 1:1 to 3:1, and preferably about 1:1.
Although gaseous hydrogen may be present, the process is normally operated in the absence of gaseous hydrogen since it appears to be unnecessary.
Advantageously, the process is, carried substantial absence of carbon dioxide.
Preferably, the process is carried out under a substantially inert atmosphere, for example nitrogen or argon.
When the product(s) from dehydrogenation of the hydrogen donor is volatile, for example boils at under 100xc2x0 C., the removal of this volatile product is preferred. The removal can be accomplished by distillation preferably at less than atmospheric pressure or by use of inert gas sparging. When reduced pressure distillation is employed, the pressure is often no more than 500 mmHg, commonly no more than 200 mmHg, preferably in the range of from 5 to 100 mmHg, and most preferably from 10 to 80 mmHg. When the product(s) from dehydrogenation of the hydrogen donor is a gaseous material, for example when formic acid is present as a hydrogen donor, the removal is most preferably accomplished by the use of inert gas sparging, with for example nitrogen.
Suitably the process is carried out at temperatures in the range of from minus 78 to plus 150xc2x0 C., preferably from minus 20 to plus 110xc2x0 C. and more preferably from minus 5 to plus 60xc2x0 C. The initial concentration of the substrate, a compound of formula (1), is suitably in the range 0.05 to 1.0 and, for convenient larger scale operation, can be for example up to 6.0 more especially 0.25 to 2.0, on a molar basis. The molar ratio of the substrate to catalyst is suitably no less than 50:1 and can be up to 50000:1, preferably between 100:1 and 5000:1 and more preferably between 200:1 and 2000:1. The hydrogen donor is preferably employed in a molar excess over the substrate, especially from 5 to 50 fold or, if convenience permits, greater, for example up to 500 fold. After reaction, the mixture is worked up by standard procedures.
During the reaction a solvent may be present, preferably a polar solvent, for example methanol, ethanol or i-propanol, more preferably a polar aprotic solvent, for example acetonitrile, dimethylformamide or dichloromethane. Conveniently, the hydrogen donor may be the solvent when the hydrogen donor is a liquid at the reaction temperature, or it may be used in combination with other solvents. In certain embodiments it is preferable to use a diluent. Diluents include non-polar solvents such as toluene. Usually it is preferred to operate in substantial absence of water, but water may be present in the reaction. If the hydrogen donor or the reaction solvent is not miscible with water and the desired product is water soluble, it may be desirable to have water present as a second phase extracting the product, pushing the equilibrium and preventing loss of product optical purity as the reaction proceeds. The concentration of substrate may be chosen to optimise reaction time, yield and enantiomeric excess.
The catalytic species is believed to be substantially as represented in the above formula. It may be employed as an oligomer or metathesis product, on a solid support or may be generated in situ.
In certain embodiments it has been found that certain catalysts are preferred for the transfer hydrogenation of imines and iminium salts. Catalysts in which A-E-B is derived from N-tosyldiamines, preferably mono-N-tosyldiamines, particularly mono-N-tosylated ethylenediamines, are preferred. Especially, M is also ruthenium (II) and R27 is an aryl group or cyclopentadienyl group, or M is iridium (I) or rhodium (I) and R27 is cyclo-octadiene, or M is iridium (III) or rhodium (III) and R27 is a cyclopentadienyl group. Further, triethylamine is preferably employed as a base, a mixture of formic acid and triethylamine in the preferred ratio of 5:2 (formic acid:triethylamine) is preferably employed as hydrogen donor. When an iminium salt is present, it is preferably a protonated imine, or is a methylated or benzylated imine with an iodide, formate or trifluoroacetate counter ion. It is believed that when Y is not a vacant site, R27 is a neutral ligand and when M is rhodium or iridium and is in valence state (I), A-E-B attaches to M by means of two dative bonds (the lone pairs of the heteroatoms in both A and B coordinate to M). However, when Y is not a vacant site, R27 is a cyclopentadienyl ligand and when M is rhodium or iridium and is in valence state (III), A-E-B attaches to M by means of one dative and one formal bond. Whereas when Y is not a vacant site, R27 is a neutral ligand and when M is ruthenium and is in valence state (II), A-E-B attaches to M by means of one dative and one formal bond.
The catalyst can be made by reacting a metal aryl, alkenyl or cyclopentadienyl halide complex with a compound of formula A-E-B as defined above or a protonated equivalent from which it may be derived, and, where Y represents a vacant site, reacting the product thereof with a base. The metal aryl or alkenyl halide complex preferably has the formula [MR27Z2]2 when M is ruthenium (II) and has the formula [MR27Z]2 when M is iridium (I) or rhodium (I), wherein R27 is an aryl or alkenyl ligand as defined above, and Z represents a halide, particularly chloride. The metal cyclopentadienyl halide complex preferably has the formula [MR27Z]2 or [MR27Z]4 when M is ruthenium (II) and has the formula [MR27Z]2 when M is iridium (III) or rhodium (III), wherein R27 is an optionally substituted cyclopentadienyl ligand as defined above, and Z represents a halide, particularly chloride.
For the preparation of the catalysts according to the present invention, a solvent is preferably present. Suitable reaction temperatures are in the range 0-100, for example 20-70xc2x0 C., often giving reaction times of 0.5-24.0 h. After reaction is complete, the catalyst may if desired be isolated, but is more conveniently stored as the solution or used soon after preparation. The solution can contain the hydrogen donor and this, if a secondary alcohol, may be present in or used as the solvent for steps (a) and/or (b). The preparation and after-handling should preferably be under an inert atmosphere, and particularly in carbon dioxide and oxygen-free conditions.
The catalyst or catalyst solution is generally treated with base either just prior to use in a transfer hydrogenation reaction, or during use. This can be accomplished by adding base to the catalyst in solution, or to the compound of formula (1) in solution, or by addition to the transfer hydrogenation reaction.
Transfer hydrogenation can be accomplished by transferring the solution of catalyst to a solution of substrate, a compound of general formula I. Alternatively a solution of substrate can be added to a solution of catalyst. Base may be pre-added to the catalyst solution and/or the substrate solution, or can be added later. The hydrogen donor if not already present in the catalyst solution may be added to the substrate solution, or may be added to the reaction mixture.
The imine and iminium salt compounds of formula (1) can generally be obtained by known literature methods. Iminium salts, for example, can be prepared by the quaternisation of imines, such as by treatment of imines with alkylating agents.
N-phosphinyl imines can be synthesised from N-hydroxy imines by treatment with a halophosphine. N-Hydroxy imines being readily available from the corresponding aldehyde or ketone by treatment with hydroxylamine. A similar approach can be used for the synthesis of certain N-sulphonylimines whereby N-hydroxy imines are treated with a halosulphoxyl compound in the presence of a base.
Alternatively, N-phosphinyl imines can be synthesised from aldehydes or ketones by treatment with phosphinic amides in the presence of a condensation reagent, such as titanium tetrachloride, and a base.
Many of the N-phosphinyl, N-sulphonyl, N-sulphoxyl and N-carboxy imines can be synthesised from aldehydes or ketones by treatment with the corresponding phosphinamide, sulphonamide, sulphoxamide or carboxamides under dehydrating conditions, such azeotropic water removal, often carried out in the presence of an acid catalyst, such as p-toluene sulphonic acid or trifluoroacetic acid, or a Lewis acid catalyst, treatments with molar equivalents or excesses of drying agents, for example molecular sieves or magnesium sulphate, or treatments with combined lewis acid and dehydrating agents such as titanium tetrachloride or titanium tetraisopropoxide.
N-Carboxy and N-sulphoxyl imines may also be prepared by reaction of ketones with aza Wittig reagents.
N-Sulphoxyl imines may also be prepared by the reaction of a organometallic derivatives of imines, such as an N-lithiated imine, with chiral sulphoxides such as menthyl p-toluene sulphinate.
N-Silylimines can be prepared form organometallic derivative of silazanes such as lithium di(trimethyl)silazamide, and ketones, or by the reaction of organometallic derivatives of imines, such as an N-lithiated imine, with a halosilane.
Furthermore, either by in situ cleavage of the R3 or R4 groups of the amines produced by the process of first aspect of present invention under the process conditions, or by further treatment by for example acid or base hydrolysis, a ready route to primary and secondary amines can be accessed.
According to a second aspect of the present invention there is provided a process for the production of primary or secondary amines 
comprising the steps of
a) generating a substrate of general formula (1) from a carbonyl compound (2), 
xe2x80x83in which X represents NR3 or (NR4R5)+Qxe2x88x92, and Qxe2x88x92 represents a monovalent anion,
b) reacting the substrate of general formula (1) with a hydrogen donor in the presence of a transfer hydrogenation catalyst, and
c) removal of R3 or R4 to give an amine of formula (3) 
wherein:
R1 and R2 each independently represents a hydrogen atom, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group, a substituted carbonyl functional group, a substituted thiocarbonyl functional group or substituted imino functional group, R1 and R2 optionally being linked in such a way as to form an optionally substituted ring;
R3 and R4 represents xe2x80x94P(O)R6R7, xe2x80x94P(O)OR8OR9, xe2x80x94P(O)OR8OH, xe2x80x94P(O)(OH)2, xe2x80x94P(O)SR10SR11, xe2x80x94P(O)SR10SH, xe2x80x94P(O)(SH)2, xe2x80x94P(O)NR12R13NR14R15, xe2x80x94P(O)NR12R13NHR14, xe2x80x94P(O)NHR12NHR14, xe2x80x94P(O)NR12R13NH2, xe2x80x94P(O)NHR12NH2, xe2x80x94P(O)(NH2)2, xe2x80x94P(O)R6OR8, xe2x80x94P(O)R6OH, xe2x80x94P(O)R6SR10, xe2x80x94P(O)R6SH, xe2x80x94P(O)R6NR12R13, xe2x80x94P(O)R6NHR12, xe2x80x94P(O)R6NH2, xe2x80x94P(O)OR8SR10, xe2x80x94P(O)OR8SH, xe2x80x94P(O)OHSR10, xe2x80x94P(O)OHSH, xe2x80x94P(O)OR8NR12R13, xe2x80x94P(O)OR8NHR12, xe2x80x94P(O)OR8NH2, xe2x80x94P(O)OHNR12R13, xe2x80x94P(O)OHNHR12, xe2x80x94P(O)OHNH2, xe2x80x94P(O)SR10NR12R13, xe2x80x94P(O)SR10NHR12, xe2x80x94P(O)SR10NH2, xe2x80x94P(O)SHNR12R13, xe2x80x94P(O)SHNHR12, xe2x80x94P(O)SHNH2, xe2x80x94P(S)R6R7, xe2x80x94P(S)OR8OR9, xe2x80x94P(S)OR8OH, xe2x80x94P(S)(OH)2, xe2x80x94P(S)SR10SR11, xe2x80x94P(S)SR10SH, xe2x80x94P(S)(SH)2, xe2x80x94P(S)NR12R13NR14R15, xe2x80x94P(S)NR12R13NHR14, xe2x80x94P(S)NHR12NHR14, xe2x80x94P(S)NR12R13NH2, xe2x80x94P(S)NHR12NH2, xe2x80x94P(S)(NH2)2, xe2x80x94P(S)R6OR8, xe2x80x94P(S)R6OH, xe2x80x94P(S)R6SR10, xe2x80x94P(S)R6SH, xe2x80x94P(S)R6NR12R13, xe2x80x94P(S)R6NHR12, xe2x80x94P(S)R6NH2, xe2x80x94P(S)OR8SR10, xe2x80x94P(S)OHSR10, xe2x80x94P(S)OR8SH, xe2x80x94P(S)OHSH, xe2x80x94P(S)OR8NR12R13, xe2x80x94P(S)OR8NHR12, xe2x80x94P(S)OR8NH2, xe2x80x94P(S)OHNR12R13, xe2x80x94P(S)OHNHR12, xe2x80x94P(S)OHNH2, xe2x80x94P(S)SR10NR12R13, xe2x80x94P(S)SR10NHR12, xe2x80x94P(S)SR10NH2, xe2x80x94P(S)SHNR12R13, xe2x80x94P(S)SHNHR12, xe2x80x94P(S)SHNH2, xe2x80x94PR6R7, xe2x80x94POR8OR9, xe2x80x94PSR10SR11, xe2x80x94PNR12R13NR14R15, xe2x80x94PR6OR8, xe2x80x94PR6SR10, xe2x80x94PR6NR12R13, xe2x80x94POR8SR10, xe2x80x94POR8NR12R13, xe2x80x94PSR10NR12R13, xe2x80x94S(O)R16, xe2x80x94S(O)2R17, xe2x80x94COR18, xe2x80x94CO2R19, or SiR20R21R22;
R5 and R38 represents a hydrogen atom, an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, or an optionally substituted heterocyclyl group;
R6 and R7 independently represent an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group or xe2x80x94Nxe2x95x90CR23R24 where R23 and R24 are as defined for R1; and
R8 to R22 each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, one or more of R1 and R6, R2 and R7, R6 and R7, R6 and R8, R6 and R10, R6 and R12, R1 and R8, R2 and R9, R8 and R9, R8 and R10, R8 and R12, R1 and R10, R2 and R11, R10and R11, R10 and R12, R1 and R12, R2 and R13, R12 and R13, R1 and R14, R2 and R15, R14 and R15, R12 and R14, R1 and R16, R1 and R18, R1 and R19, R1 and R20, R2 and R21, R20 and R21 and R21 and R22 optionally being linked in such a way as to form an optionally substituted ring(s).
Preferably, when a substrate of formula (1) or an amine of formula (3) comprises one or more optionally substituted ring(s), it is preferred that only one or more of R1 and R2, R6 and R7, R8 and R9, R10 and R11, R12 and R13, R14 and R15, R12 and R14, R20 and R21 and R21 and R22 are optionally linked in such a way as to form an optionally substituted ring(s).
When the substrate of general formula (1) is an imine [i.e. Xxe2x95x90NR3], the step of generating the substrate of general formula (1) from a carbonyl compound (2), 
is preferably accomplished by treating a carbonyl compound of formula (2) with a substituted amino compound R3NH2.
When the substrate of general formula (1) is an iminium salt [i.e. X=(NR4R5)+Qxe2x88x92], the step of generating the substrate of general formula (1) from a carbonyl compound (2), 
is preferably accomplished by treating a carbonyl compound of formula (2) with a substituted amino compound R4NH2 and quaternizing or protonating the resulting imine to give the iminium salt.
In certain embodiments, particularly in the generation of imines or iminium salts wherein R3 or R4 contain a phosphorous oxygen double bond, it is preferable in the step of generating the substrate of general formula (1) from a carbonyl compound (2) first to treat the carbonyl compound of formula (2) with hydroxylamine to generate the corresponding oxime, and then to react the oxime with an activated species containing the groups that will form R3 or R4, such as halo derivative, for example CIP(Ph)2.
When reacting the substrate of general formula (1) with a hydrogen donor in the presence of a transfer hydrogenation catalyst to give an amine, the step is carried out in accordance with reference to the first aspect of the present invention as described herein before.
The step of removal of the R3 or R4 may be carried out by any means which is generally known to cleave groups represented by R3 or R4 which are attached to an amine. Preferably, R3 or R4 are removed either by treatment with acid, treatment with base, hydrogenation or treatment with nucleophilic agents, such as fluoride, the method employed being selected according to the nature of R3 or R4.
In many embodiments, R3 or R4, especially when R3 or R4 is a group selected from xe2x80x94P(O)R6R7, xe2x80x94P(O)OR8OR9, xe2x80x94P(O)OR8OH, xe2x80x94P(O)(OH)2, xe2x80x94P(O)SR10SR11, xe2x80x94P(O)SR10SH, xe2x80x94P(O)(SH)2, xe2x80x94P(O)NR12R13NR14R15, xe2x80x94P(O)NR12R13NHR14, xe2x80x94P(O)NHR12NHR14, xe2x80x94P(O)NR12R13NH2, xe2x80x94P(O)NHR12NH2, xe2x80x94P(O)(NH2)2, xe2x80x94P(O)R6OR8, xe2x80x94P(O)R6OH, xe2x80x94P(O)R6SR10, xe2x80x94P(O)R6SH, xe2x80x94P(O)R6NR12R13, xe2x80x94P(O)R6NHR12, xe2x80x94P(O)R6NH2, xe2x80x94P(O)OR8SR10, xe2x80x94P(O)OR8SH, xe2x80x94P(O)OHSR10, xe2x80x94P(O)OHSH, xe2x80x94P(O)OR8NR12R13, xe2x80x94P(O)OR8NHR12, xe2x80x94P(O)OR8NH2, xe2x80x94P(O)OHNR12R13, xe2x80x94P(O)OHNHR12, xe2x80x94P(O)OHNH2, xe2x80x94P(O)SR10NR12R13, xe2x80x94P(O)SR10NHR12, xe2x80x94P(O)SR10NH2, xe2x80x94P(O)SHNR12R13, xe2x80x94P(O)SHNHR12, xe2x80x94P(O)SHNH2, xe2x80x94P(S)R6R7, xe2x80x94P(S)OR8OR9, xe2x80x94P(S)OR8OH, xe2x80x94P(S)(OH)2, xe2x80x94P(S)SR10SR11, xe2x80x94P(S)SR10SH, xe2x80x94P(S)(SH)2, xe2x80x94P(S)NR12R13NR14R15, xe2x80x94P(S)NR12R13NHR14, xe2x80x94P(S)NHR12NHR14, xe2x80x94P(S)NR12R13NH2, xe2x80x94P(S)NHR12NH2, xe2x80x94P(S)(NH2)2, xe2x80x94P(S)R6OR8, xe2x80x94P(S)R6OH, xe2x80x94P(S)R6SR10, xe2x80x94P(S)R6SH, xe2x80x94P(S)R6NR12R13, xe2x80x94P(S)R6NHR12, xe2x80x94P(S)R6NH2, xe2x80x94P(S)OR8SR10, xe2x80x94P(S)OHSR10, xe2x80x94P(S)OR8SH, xe2x80x94P(S)OHSH, xe2x80x94P(S)OR8NR12R13, xe2x80x94P(S)OR8NHR12, xe2x80x94P(S)OR8NH2, xe2x80x94P(S)OHNR12R13, xe2x80x94P(S)OHNHR12, xe2x80x94P(S)OHNH2, xe2x80x94P(S)SR10NR12R13, xe2x80x94P(S)SR10NHR12, xe2x80x94P(S)SR10NH2, xe2x80x94P(S)SHNR12R13, xe2x80x94P(S)SHNHR12, and xe2x80x94P(S)SHNH2, are removed by treatment with acid, such as gaseous hydrogen chloride, aqueous hydrochloric acid, hydrochloric acid/alcohol mixtures, acetic acid/formic acid/water mixture, trifluoroacetic acid, p-toluenesulphonic acid, or other mineral acids. Preferably, gaseous hydrogen chloride is bubbled through a solution of the phosphorous substituted amine, or the phosphorous substituted amine is treated with an hydrochloric acid solution to effect the cleavage of the nitrogen-phosphorous bond.
When R3 or R4 is a group represented by CO2R19 treatments with acids or reductive methods may be used to remove the R3 or R4 group. When R19 is a benzyl group, reductive methods such as hydrogenation in the presence of palladium or charcoal and dissolving metal reductions, or treatment with strong acid, such as hydrogen bromide/acetic acid mixtures, may be employed. When R19 is a t-butyl group treatment with an acid such as p-toluenesulphonic or trifluoroacetic acid in an organic solvent such as alcohols, ethers or acetonitrile may be employed. When R19 is a methyl group, more forcing conditions may be required such as treatments with hydrazine or alkali metal hydroxides.
When R3 or R4 is a group represented by COR18, the R3 or R4 group may be removed by acid or base hydrolysis.
When R3 or R4 is a group represented by xe2x80x94S(O)2R17, treatments with acids or reductive methods may be used to remove the R3 or R4 group. When R17 is a methyl group hydride reductions, for example using lithium aluminium hydride, or dissolving metal reductions may be employed. When R17 is a p-tolyl group treatment in strong acid, such as trifluoroacetic acid in methanol or 6M hydrocholoric acid, may be employed. When R17 is a trimethylsilylethyl group treatment with an alkali metal fluoride, preferably caesium fluoride, may be employed.
When R3 or R4 is a group represented by SiR20R21R22, treatments with acids or alkali metal fluorides may be used to remove the R3 or R4 group.